1. Field of the Invention
This invention relates to the use of diterpene compounds, in particular hypoestoxides, derivatives and agonists thereof for antiviral therapy.
2. Background Art
The interactions between viruses and the host immune system are not only complex and fascinating but also critical in determining the outcome of infection and strategies for its prevention. The goal of antiviral chemotherapy is to inhibit replication of the viral genome without affecting the DNA of the cell.
Of the large number of agents under development for the treatment of herpes virus infections [herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV)], only ten have apparently reached clinical development (Alrabiah FA and Sacks, SL; Drugs 1996:52(1):17-32). Although aciclovir is the treatment of choice in herpes simplex encephalitis (HSV-1), mortality and morbidity remain problematic (Skoldenberg B; Scand. J. Infect Dis Suppl 100:8-13, 1996). The same can be said about interferon-alpha (IFN-.alpha.) and interferon-beta (IFN-.beta.). Although both IFNs have considerable antiviral and immunomodulatory effects, their success as antiviral agents in humans has been hindered by their dose-limiting side effects (Balkwill, FR. Interferons; Lancet 1989;1:1060-1063). HSV-2 is the most common infective cause of genital ulceration in developed countries. Currently, 1 in 5 (20%) teenage adults in the United States is infected with genital herpes. A range of antiviral agents has become available since the early 1980s which can reduce disease severity, but HSV infection is life-long and, once established, there is no treatment which will eliminate it (Brugha, R. et al. Int. J. Epidemiol 1997;26:698-709). Therefore, there is a tremendous need to develop new approaches and agents to eliminate HSV infection.
The number of human immunodeficiency virus type 1 (HIV-1)-infected individuals is currently estimated at 1-2 million in the United States, with a worldwide incidence of approximately 20 million. By the year 2000, it is estimated that more than 3 million Americans will be infected with HIV-1.
Until recently, treatment of HIV-1 infection was limited to the use of nucleoside inhibitors of the viral enzyme reverse transcriptase (RTI). While these agents initially offered promise, they have only modest antiviral activity and the benefits of treatment are limited by the emergence of drug resistance and dose-limiting toxic effects (McDonald CK et al. Arch Intern Med 1997;157(9):951-959). Although treatment of HIV with nucleoside analog RTIs and protease inhibitors forms the backbone of anti-HIV therapy, non-nucleoside RTIs, immune modulators, and new entries in existing classes of pharmacologic agents hold promise for the future (Hartman AF, Prim Care 1997;24(3):531-560). Because combination therapy with two, three, or more agents has become the standard of care, additive toxicities have become a major problem.